Gene expression and function can be modified by variations in copy number. Some variations are found among normal individuals, others occur in the course of normal processes in some species, and still others participate in causing or exacerbating various diseases. For example, many defects in human and non-human animal development are due to gains and losses of chromosomes and chromosomal segments that occur prior to or shortly after fertilization, whereas DNA dosage alterations that occur in somatic cells are often contributors to cancer. Therefore, detection of such aberrations, and interpreting them within the context of broader knowledge, facilitates identification of critical genes and pathways involved in biological processes and diseases, and provides clinically relevant information, such as in identifying efficacious drug regimes.
Copy-number variation presents an opportunity in medical genetics. The importance of normal copy-number variation involving large segments of DNA has been unappreciated until recently. Although methods such as array CGH (array-based comparative genomic hybridization) have established the existence of copy number polymorphisms in human and non-human animal genomes, the picture of this normal variation is incomplete. In results reported to date, measurement noise and resolution have restricted detection to polymorphisms that involve genomic segments of many kilobases or larger, genome coverage has been far from comprehensive, and the population has not been adequately sampled.
A comprehensive understanding of these normal variations is of intrinsic biological interest and is important for the proper interpretation of data and its relation to phenotype. Furthermore, understanding the copy number polymorphisms that are detectable by a particular technique is important so that normal variations are not falsely associated with disease or drug response, and, conversely, to determine if some so-called normal variation can underlie phenotypic characteristics such as disease susceptibility.
As such, the utilization of copy number variants, which can be detected with technologies such as array CGH, genotyping microarrays, and sequencing, is making clear the essential need to understand normal variation throughout human and non-human animal populations. The present invention provides compositions and methods that fill this unmet need for understanding normal variation thus facilitating personalized medicine.
Because of the magnitude of the number of genetic variants that exist and the existence of normal copy number variants and other types of normal genetic variants, sophisticated analysis tools are often used to interpret whether a genetic variant is a causative mutation of a disease or condition. There is thus the need for methods and tools to permit an accurate interpretation or diagnosis of genetic variants of all sizes and types.